SMARCA4/BRG1 Is a Novel Prognostic Biomarker Predictive of Cisplatin-Based Chemotherapy Outcomes in Resected Non-Small Cell Lung Cancer.
SMARCA4/BRG1 Is a Novel Prognostic Biomarker Predictive of Cisplatin-Based Chemotherapy Outcomes in Resected Non-Small Cell Lung Cancer.
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DOI：
10.1158/1078-0432.ccr-15-1468
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发表时间：
2016-05-15
期刊：
影响因子：
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通讯作者：
Chakravarti A
中科院分区：
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作者：
Bell EH;Chakraborty AR;Mo X;Liu Z;Shilo K;Kirste S;Stegmaier P;McNulty M;Karachaliou N;Rosell R;Bepler G;Carbone DP;Chakravarti A
迫切需要识别预测性生物标志物，以改善从铂类化疗中获得最大益处的患者的选择。我们假设 SMARCA4/BRG1（一种已知的转录和 DNA 修复调节因子）的表达降低是 NSCLC 对铂类辅助治疗敏感性增加的新型预测生物标志物。使用来自主任挑战肺研究 (n=440) 的基因表达微阵列测试预后价值。使用顺铂/长春瑞滨辅助试验的 JBR.10 试验的对照组和治疗组的基因表达微阵列 (n=133) 确定 SMARCA4 的预测意义。使用Kaplan-Meier方法和对数秩检验来估计和测试表达组和治疗组之间总生存（OS）和疾病特异性生存（DSS）的概率差异。使用多变量 Cox 回归模型，同时调整其他临床协变量。在Director's Challenge 研究中，与高表达和中等表达相比，SMARCA4 表达减少与较差的 OS 相关（分别为 P<0.001 和 P=0.009）。在多变量分析中，与低表达相比，SMARCA4 高表达预测死亡风险降低（HR=0.6，95% CI：0.4–0.8，P=0.002）。在 JBR.10 试验中，仅在接受顺铂/长春瑞滨辅助治疗时，仅在 SMARCA4 表达低的患者中观察到五年 DSS 有所改善（HR=0.1，95% CI：0.0–0.5，P=0.002 [低]；HR 1.0，95% CI：0.5–2.3，P=0.92 [高]）。交互作用测试非常显着（P=0.01）。 SMARCA4/BRG1 的低表达与较差的预后显着相关；然而，它是一种新型的重要预测生物标志物，可提高 NSCLC 对铂类化疗的敏感性。
Identification of predictive biomarkers is critically needed to improve selection of patients who derive the most benefit from platinum-based chemotherapy. We hypothesized that decreased expression of SMARCA4/BRG1, a known regulator of transcription and DNA repair, is a novel predictive biomarker of increased sensitivity to adjuvant platinum-based therapies in NSCLC. The prognostic value was tested using a gene expression microarray from the Director’s Challenge Lung Study (n=440). The predictive significance of SMARCA4 was determined using a gene expression microarray (n=133) from control and treatment arms of the JBR.10 trial of adjuvant cisplatin/vinorelbine. Kaplan-Meier method and log-rank tests were used to estimate and test the differences of probabilities in overall survival (OS) and disease-specific survival (DSS) between expression groups and treatment arms. Multivariate Cox regression models were used while adjusting for other clinical covariates. In the Director’s Challenge Study, reduced expression of SMARCA4 was associated with poor OS compared to high and intermediate expression (P<0.001 and P=0.009, respectively). In multivariate analysis, compared to low, high SMARCA4 expression predicted a decrease in risk of death (HR=0.6, 95% CI: 0.4–0.8, P=0.002). In the JBR.10 trial, improved five-year DSS was noted only in patients with low SMARCA4 expression when treated with adjuvant cisplatin/vinorelbine (HR=0.1, 95% CI: 0.0–0.5, P=0.002 [low]; HR 1.0, 95% CI: 0.5–2.3, P=0.92 [high]). An interaction test was highly significant (P=0.01). Low expression of SMARCA4/BRG1 is significantly associated with worse prognosis; however, it is a novel significant predictive biomarker for increased sensitivity to platinum-based chemotherapy in NSCLC.